Alzheimer's disease (AD) presents an enormous burden to society that will increase substantially in the next decades as the population ages. Because of this, it is essential to develop a more complete understanding of the underlying disease mechanisms to identify preventive and therapeutic strategies. AD is characterized by synergistic interactions between inflammation, amyloid beta (A2) peptide accumulation, and neuronal network dysfunctions that contribute to eventual cognitive decline and memory loss. In the search for preventive and therapeutic strategies, the pre-clinical inflammatory response may represent a promising target for intervention. Studies show that the use of non-steroidal anti-inflammatory drugs (NSAIDs), a class of drugs that inhibit the synthesis of pro-inflammatory prostaglandins such as PGE2, is associated with a significantly reduced risk of developing AD in normal aging populations. However, later administration in symptomatic AD patients is not effective in reducing cognitive decline. These human data suggest that early inflammatory changes play a significant role in the development of AD. This proposed study aims to determine the cellular and molecular mechanisms of the early inflammatory phenotype that lead to subsequent neuronal toxicity. This study will use established mouse models of AD that recapitulate the early inflammation, A2 accumulation, and neuronal network dysfunction seen in human AD. Specifically, the first aim of this proposal will test the hypothesis that early-life anti- inflammatory treatment in AD model mice prevents later synaptic dysfunction, behavioral decline, and A2 accumulation. While previous studies have shown reduced A2 deposition using NSAID treatment at late ages, the proposed study will improve and expand this work by testing the effects of early-life treatment on inflammatory phenotypes from both the central nervous system, mediated by microglial cells, and from peripheral blood mediators of inflammation, which are known to be elevated in human AD. Downstream of prostaglandin production, the PGE2 EP2 receptor may be a more specific molecular target in the search for strategies that prevent and reduce inflammation in AD. The EP2 receptor plays a crucial pro-inflammatory role in a mouse model of AD and contributes to oxidative damage, synaptic toxicity, and increased A2 deposition in this model, but the cellular substrates and molecular mechanisms of EP2-induced neuro- inflammation remain unknown. The second aim of this proposal will test the hypothesis that the microglial EP2 receptor drives the inflammatory response and subsequent phenotypes in AD model mice, using a genetic strategy to delete the EP2 receptor specifically in the microglia of AD model mice. Specifying these cellular and molecular mechanisms will improve our understanding the neuro-toxic inflammatory pathways in AD. This will be a crucial step in developing preventive and therapeutic strategies for AD that protect health and prevent disease in the aging world population.